Pulmonary fibrosis is a devastating disease for which there is no effective treatment or cure. It may be idiopathic, related to a systemic illness such a sarcoidosis or connective tissue disease, or be related to occupational exposures. Unfortunately the pathophysiology of pulmonary fibrosis remains poorly understood. It is believed to be the result of chronic inflammation and immune activation that leads to increased deposition of fibroblasts and extracellular matrix proteins, but what cells are involved in promoting chronic inflammation and fibrosis are not known. T cells are known to regulate the immune system, but their role in pulmonary fibrosis is unclear. Previous studies looking at the role of T cells in the development of fibrosis have utilized mice that are globally deficient in T cells and found disparate results. In some studies mice lacking T cells develop decreased inflammation and fibrosis compared to wildtype mice; however other studies have found increased fibrosis or no difference. It is known that T cells have a number of different functions in regulating the immune system, and different CD4+ T cell subsets secrete specific cytokines and are involved in specific aspects of disease. Th1 cells produce IFN-? and target intracellular pathogens, and Th2 cells produce the cytokines IL-4 and IL-13 and target extracellular pathogens and are involved in asthma. Th17 cells produce the cytokine IL-17 and are associated with multiple sclerosis and connective tissue diseases. Regulatory T cells produce IL-10 and are involved in immune suppression and tolerance. Previous studies have explored the role of some of these cytokines in the development of fibrosis and found that loss of Th1 cytokines are associated with increased fibrosis, while loss of the Th2 and Th17 cytokines is associated with decreased fibrosis. However, these experiments utilized whole body knockouts of the target cytokine, and because these cytokines are not unique to T cells, the results may be independent of T cell function. Our collaborator Jonathan Powell has shown that mTOR regulates differentiation of helper T cells through mTORC1 and mTORC2 signaling. Mice lacking mTORC1 signaling within CD4+ T cells are unable to produce Th1 and Th17 cells, and those lacking mTORC2 signaling within CD4+ T cells are unable to produce Th2 cells. Using mice lacking mTORC1 signaling or mTORC2 signaling within only CD4+ cells, we will evaluate the role that CD4+ T cell subsets are playing in the development of pulmonary fibrosis, using intraperitoneal bleomycin as our model of fibrosis. We will then attempt to prevent the development of fibrosis by enhancing the Th1 response using intranasal vaccinia. These experiments will allow us to explore the role of CD4+ T cells in the development of pulmonary fibrosis with the aim of providing novel therapeutic targets.